This application is a 371 of PCT/EP99/09462 filed Dec. 3, 1999.
The present invention relates to a process for producing agglomerates with a core/shell structure and to the agglomerates obtainable thereby.
Agglomeration is to be understood here to be a process in which fine-pile substances are clumped together by wetting with a liquid with simultaneous mechanical agitation to give conglomerates, i.e. pellets or granules. The resulting agglomerates are assemblages of particles in which the original particles are not completely fused together, it being possible, for example by microscopic examination, still to recognize the outlines of some of the individual particles. An agglomerated material has numerous advantages over the fine-particle starting material. Thus, certain properties such as strength, size, shape and porosity can be adjusted in a defined manner, which is noticeably advantageous on storage, transport and metering. Any homogeneities are prevented, the bulk properties are improved and the formation of dust during packaging and transferring is reduced. This increase in quality makes the additional agglomeration processing step justifiable in the manufacture of numerous products such as drugs.
In what is called agitative agglomeration there is automatic attachment of the particles together on wetting with liquid on the reaction of interfacial forces while the material is agitated mechanically.
A special type of agitative agglomeration is rewetting agglomeration. The basis for this is a 3-phase mixture which consists of a fine material to be agglomerated and of a suspending liquid and a binder liquid which must not be miscible with one another. The binder liquid must have the property of wetting the suspended material better than does the suspending liquid. The fine material to be agglomerated is present in suspended form in the suspending liquid. The binder liquid is then introduced and interacts with the fine particles and leads to particle size enlargement. The granules which are formed are removed from the reusable suspending liquid, for example using a filtration apparatus.
Many drugs can be administered in solid form as agglomerates. These dissolve in the body over a certain period. The rate of dissolution is determined by the area of the drug available for attack by body fluid, i.e. the surface area of the drug. If the surface area is reduced by the dissolution process, a smaller amount of active ingredient is released per unit time. However, for most applications a constant rate of release of active ingredient is desired. One aspect of the present invention is therefore based on the object of indicating a process for producing agglomerates which show essentially uniform release of active ingredient throughout the dissolution period.
It is often desirable to produce solid drug forms with more than one active ingredient, with the active ingredients being released at different times.
Another aspect of the invention is therefore based on the object of indicating a process for producing agglomerates which contain different active ingredients which are released successively.
DE-A 44 00 295 describes a spherical granulum which is prepared by introducing lactose particles into a granulating and coating apparatus equipped with a horizontal rotating disk having a flat contacting surface towards the granula, and spraying a lactose solution during rotation of the rotating disk. The granulum is useful as carrier for drugs and foodstuff.
We have found that the above objects are achieved by a process for producing agglomerates with a core/shell structure, in which i) initial agglomerates containing a first particulate solid are prepared; ii) a second particulate solid is agglomerated in the presence of the initial agglomerates with the addition of a binder liquid to give second stage agglomerates and, where appropriate, iii) an nth (where n is a positive integer xe2x89xa73) solid is agglomerated in the presence of the (nxe2x88x921)th stage agglomerates with the addition of a binder liquid to give nth stage agglomerates. Step iii) is optional. It can, if required, be repeated one or more times. The value of n starts at 3 and increases by 1 after every repetition.